Sulfonylurea is a Non-competitive inhibitor of Acetohydroxyacid Synthase from Mycobacterium tuberculosis

Abstract

Acetohydroxyacid synthase (AHAS EC2.2.1.6) catalyses the first step in the biosynthesis of branched-chain aminoacids (BCAAs). AHAS catalyzes the condensation of two molecules of pyruvate to form 2-acetolactate in the biosynthasis of valine and leucine or the condensation of pyruvate and 2-ketobutyrate to form 2-aceto-2-hydroxybutyrate in the biosynthesis of isoleucine. AHAS consists of two subunits, the catalytic subunits and the regulatory subunits. The enzymatic activity of AHAS is produced from the catalytic subunit, while the regulatory subunit affects feedback regulation and activation of the catalytic subunit. AHAS repuires three cofactors for activity thiamin diphospate (ThDP), divalent metal ion (usually Mg2+), and flavin adenine dinucleotide(FAD). The first two cofactors are typical for the ThDP- depenent enzymes in the catalysis. In this study, we observed that inhibition of AHAS from Mycobacterium tuberculosis by sulfonylurea in non-cpmpetitive. So we can, at least, estimate that the sulfonylurea can bind to either free enzyme or substrate binding enzyme in the active site. This approach for understanding the mechanism of inhibition will extend the possibilities for the design of new inhibitors and the development of new anti-TB drugs.